Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis is transmitted mainly through air, affecting most often the lungs. When persons with pulmonary TB cough they produce tiny droplet nuclei containing M. tuberculosis, which remain suspended in air for a prolonged period of time. A person who breathes the air containing the aforesaid droplet nuclei containing M. tuberculosis can become infected with TB.
TB, one of the three major infectious diseases in the priority list of the World Health Organization's (WHO) agenda kills about two million people around the world every year. About six million new cases are reported every year and nearly 20% of adult deaths and 6% of infant deaths are attributable to the disease (C. Dye et. al., J. Am. Med. Ass., 1999, 282, 677-686). About a billion people are expected to be affected by TB by the year 2020, with 35 million likely to succumb to the disease (WHO Fact Sheet No. 104, Global Alliance for TB Drug Development—Executive Summary of the Scientific Blueprint for TB Development www.who.int/inf-fs/en/fact104).
With the emergence of the AIDS epidemic and the increase in cases of HIV coupled with TB as well as the continued resistance of M. tuberculosis to isoniazid and rifampicin, the two most powerful anti-tubercular drugs available today there is an urgent need for new anti-tubercular drugs to combat the killer disease (S. H. E. Kaufmann et. al., Trends Microbiol., 1993, 1, 2-5 B. R. Bloom et. al., N. Engl. J. Med., 1998, 338, 677-678).
Although, many new compounds are becoming available for fighting a number of infectious diseases, the number of such compounds having antimycobacterial activity are few. This could partly be due to the complexity of research involved and partly due to business considerations (B. N. Roy et. al., J. Ind. Chem. Soc., April 2002, 79, 320-335 and references cited therein).
However, renewed thrust in research in the last decade has resulted in development of new antimycobacterial compounds,    a) differing widely in structures,    b) having different mode/mechanism of action,    c) possessing favourable pharmacokinetic properties,    d) which are safe and have low incidence of side-effects, and    e) which provide a cost-effective dosage regimen.
Among the aforesaid new compounds, the oxazolidinones first developed during the mid-1980s (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681 and 1990, 33, 2569-2578; C-H Park et. al., J. Med. Chem., 1992, 35, 1156-1165) are a unique class in themselves. The in vivo results for some of the oxazolidinones show that they are active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, including resistant strains such as methicillin-resistant Staphylococcus aureus [MRSA], methicillin-resistant Streptococcus epidermidis [MRSE], penicillin-resistant Streptococcus pneumoniae [PRSP], vancomycin-resistant enterococci [VRE], etc. (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The oxazolidinones inhibit bacterial protein synthesis at a very early step in the initiation of complex formation involved in the process of translating mRNA into protein. The oxazolidinones, in general, are not cross-resistant with any known antibiotic because of this unique mechanism (D. C. Eustice et. al., Antimicrob. Agents Chemother., 1988, 32, 1218 and Biochem. Biophys. Res. Commun., 1988, 150, 965).
A feature of the oxazolidinone molecule is that only those compounds, which are enantiomers with a (5S)-acetamidomethyl configuration in the left side of the molecule are known to exhibit antibacterial activity (W. A. Gregory et. al., J. Med. Chem., 1989, 32, 1673-1681). Another feature is that most of such antibacterial compounds invariably carry a (substituted) phenyl ring attached to the nitrogen atom of the oxazolidinone ring in the right side of the molecule (B. Riedl et. al., Exp. Opin. Ther. Patents., Ashley Publications Ltd., 1999, 9 (5), 625-633 and the references contained therein).
The most promising compound among the N-phenyl oxazolidinones, which has been approved for human use is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidin-yl]methyl]-acetamide), commonly known as linezolid (M. Barbachyn et. al., WO 995/07271). Linezolid possesses good in vitro and in vivo potency against most of the Gram-positive bacteria, including resistant strains (Drugs of the Future, 1996, 21(11), 1116-1123).
The left hand side i.e. position 5- and the right hand side i.e. position 3-respectively of the oxazolidinone ring nucleus allows for many variations and has resulted in the discovery of a large number of compounds having antimicrobial and antibacterial properties. Such representative compounds, albeit not meant to be limiting are disclosed in the following prior art references. These are    i) U.S. Pat. No. 4,942,183 (Gregory et. al.) and U.S. Pat. No. 4,948,801 (Carlson et. al.) collectively disclose certain 3-substituted phenyl-5-aminomethyl oxazolidinones, possessing useful antibacterial activity.    ii) U.S. Pat. No. 5,529,998 (Habich et. al.) discloses certain 3-benzoxazoyl- and benzothiazolyl-5-acetyl amino methyl oxazolidinones, useful as antibacterial medicaments.    iii) U.S. Pat. Nos. 5,565,571, 5,654,428, 5,756,732, 5,801,246 and 5,929,248 (Barbachyn et. al.) collectively disclose several substituted aryl and heteroaryl phenyloxazolidinones carrying an acetyl aminomethyl function at the 5-position, specifically oxazolidinones having an aryl or heteroaryl group at the para position of the 3-phenyl ring and additional substituents at the meta positions of the 3-phenyl ring, which are useful as antibacterials.    iv) U.S. Pat. No. 5,652,238 (Brickner et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a hydroxyl acetyl piperazine moiety, active against various Gram-positive bacteria such as staphylococci, pneumococci and enterococci, as well as anerobic organisms such as bacteroides and clostridia species as well as acid-fast organisms such as Mycobacterium tuberculosis.     v) U.S. Pat. No. 5,684,023 (Riedl et. al.) discloses certain 3-benzofuranyl- and benzothienyl oxazolidinones, carrying an azido, hydroxy or acetyl aminomethyl group at the 5-position, useful as antibacterial medicaments.    vi) U.S. Pat. No. 5,688,792 (Barbachyn et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a (substituted)-morpholine. Such compounds are useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.    vii) U.S. Pat. No. 5,719,154 (Tucker et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the said substitution being a pyrimidinyl or pyradazinyl group. Such compounds are useful as antimicrobial agents.    viii) U.S. Pat. No. 5,736,545 (Gadwood et. al.) discloses certain 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a five membered heterocycle ring, in particular an azolyl ring. Such compounds are useful in the treatment of microbial infections.    ix) U.S. Pat. No. 5,792,765 (Riedl. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-substituted phenyloxazolidinones, the substitution being a heterocyclic moiety, useful as antibacterial medicaments.    x) U.S. Pat. No. 5,861,413 (Habich et. al.) discloses certain 2-oxo and 2-thio-1,2-dihydroxyqoinolinyl-1-oxazolidinones, useful as antibacterial medicaments.    xi) U.S. Pat. No. 5,880,118 (Barbachyn et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted thiomorholine moiety i.e. oxazine and thiazine derivatives, useful for treatment of microbial infections caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp.    xii) U.S. Pat. No. 5,910,504 and U.S. Pat. No. 6,124,334 (Hutchinson et. al.) collectively disclose certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones substituted at the para position of the 3-phenyl ring with a heteroaromatic moiety, which is five membered having one to four nitrogen atoms or alternatively, a benzoannulated five-membered heteroaromatic ring having one to four nitrogen atoms, useful as antibacterials.    xiii) U.S. Pat. No. 6,069,160 (Stolle et. al.) discloses certain substituted 5-acetyl aminomethyl-3-benzocyclopentaneoxazolidinones, containing an heteroatom, useful as antibacterial medicaments.    xiv) U.S. Pat. No. 6,227,868 B1 and U.S. Pat. No. 6,410,728 (Sciotti et. al.) collectively disclose certain 5-acetyl aminomethyl-3-phenyloxazolidinones carrying an acetylenic moiety on the 3-phenyl ring, useful for treating bacterial infections, psoriasis, arthritis and toxicity due to chemotherapy.    xv) WO 93/23384 (Hutchinson et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, useful for treatment of microbial infections caused by staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.     xvi) WO 97/10223 (Gadwood et. al.) discloses certain substituted 5-acetyl aminomethyl-3-aminoaryl oxazolidinone N-oxide compounds, which are exceedingly water soluble and useful in preparation of pharmaceutical compositions for combating a number of human and veterinary pathogens, staphylococci, streptococci, as well as anaerobic organisms such as bacteroides and clostridia species and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium, Mycobacterium spp. and Mycoplasma spp.    xvii) WO 98/01446 and WO 98/01447 (Betts et. al.) collectively disclose certain substituted 5-acetyl aminomethyl3-phenyloxazolidinones, substituted at the para position of the 3-phenyl ring with a substituted piperazine moiety, the substitution being a six-membered heteroaryl ring containing two or three ring nitrogen atoms as the only ring heteroatoms, useful as antibacterial agents.    xviii) WO 99/02525 (Thomasco et. al.) discloses certain substituted 5-acetyl aminomethyl-3-phenyloxazolidinones, substituted by a thiadiazolyl or oxadiazolyl moiety, useful as antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive and Gram-negative aerobic bacteria.    xix) WO 99/37630 (Gordeev et. al.) discloses oxazolidinone combinatorial libraries, compositions containing the same and methods of preparation thereof involving solid phase synthesis, which provides the said compounds for high-throughput screening.    xx) WO99/37641 (Bartel. et. al.) discloses certain substituted 5-acetyl aminomethyl-3-bicyclene-substituted oxazolidinones, useful as antibacterial medicaments.    xxi) WO 01/09107 (Gordeev et. al.) discloses certain 3-heteroaryl-5-acetyl aminomethyl oxazolidinones, substituted by a thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl and alkylthiocarbonyl group, useful in treating or preventing an infectious disorder in humans or animals.    xxii) WO 01/42242 (Paget et. al.) discloses certain substituted 5-acetyl aminomethyl 3-substituted phenyloxazolidinones, the substitution being a bicyclic heterocyclic system, useful as antibacterial agents.    xxiii) WO 02/06278 (Mehta et. al) discloses certain substituted 3-phenyl oxazolidinones and to process for synthesis of the same, the said compounds useful as antibacterial agents, effective against a large number of human and veterinary pathogens, including Gram-positive bacteria and acid fast organisms such as Mycobacterium tuberculosis.     xxiv) WO 02/20515 (Madar et. al.) discloses heterocyclic phenyloxazolidinones, useful for treating bacterial infections.
However, only a few of the disclosures described hereinbefore provide compounds that can be used as antimycobacterials, while most of the others are silent about the antimycobacterial activity of the disclosed compounds.
A need, therefore, exists for new compounds possessing potent antimycobacterial properties for treatment of TB, which as mentioned hereinearlier is assuming alarming proportions.